For most drugs, and especially for those with cytotoxic side effects, the ideal pharmacokinetic profile will be one wherein the drug concentration reached therapeutic levels without exceeding the maximum tolerable dose and maintains these concentrations for extended periods of time. Encapsulating or conjugating a drug in a biodegradable polymer matrix provides one such way to achieve this desirable end. Polymers could deliver the drug locally and systemically, and do so in a sustained manner, over prolonged period of time. This reduces need for multiple ingestion and better patient compliance. It is also believed that stability of the drug increases since it is not exposed to the physiological conditions in-vivo. Over the last several decades, the technology of polymeric drug delivery has been studied in details (Reviews: K. Al-Tahami and J. Singh, Recent Patents on Drug Delivery & Formulation, 1 (2007) 65-71; V. R. Sinha and L. Khosla, Drug Dev. Ind. Pharm., 24 (1998)1129-1138; R. Langer, Nature, 392(1998) 5-10; W. R. Gombotz and D. K. Pettie, Bioconjug. Chem., 6 (1995) 332-351), and several commercially successful products are now available in the market. Both, non-degradable and degradable polymers can be used for drug delivery purposes. However, the latter type is preferred since the non-degradable variety would require removal of the drug depleted polymer by surgery following treatment. In case of degradable polymers, it is important to ensure that the constituent monomers are not toxic.
Most commonly used biodegradable polymers are Polylactide (PLA) and Poly(Lactide-co-Glycolide) (PLGA) [George Boswell and Richard Scribner, U.S. Pat. No. 3,773,919 (1970); R. S. Tuan, S. S. Lin, U.S. Pat. No. 5,281,419 (1994)]. Although using PLA and PLGA based polymers is advantageous due to their historic use and acceptance, commercialization of newer products based on these polymers may be difficult since more than 500 patents have been issued for various applications of these polymers. PLA and PLGA polymers also have inherent limitations in terms of flexibility for applications. Due to this, several polyesters, polyamides, and polyesteramides (PHB, PBS, PEA, TPA, PHBV, PBSA, PBAT) have found their way as second generation biodegradable polymers. Some of these and other new players are continuing to be tested and under development, e.g., natural and synthetic Polyketals [M. I. Papisov, US Patent Application 20100150832 (2010); Murthy at al., Biomaterials, 31 (2010) 810-817; Benz et al., U.S. Pat. No. 7,741,375 (2010)], Polyorthoesters [Heller et al., Eur. J. Pharm. Biopharm., 50 (2000)121-128], Polyphosphazines [H. R. Allcock, et al., Macromolecules, 16 (1983) 1401; H. R. Allcock, Advanced Materials, 6 (1994)106], Polyanhydrides [L. Shieh, et al., J. Biomed. Mater. Res., 28 (1994) 1465-1475], Polyphosphoesters [M. Richards, et al., J. Biomed. Mater. Res., 25 (1991)1151], Polyesters [R. Jain, et al., Drug Dev. Ind. Pharm., 24 (1998) 703-727]. Hydrogels that can respond to a variety of physical, chemical and biological stimuli have been used to design of closed-loop drug-delivery systems [O. Pillai and R. Panchagnula, Curr. Opin. Chem. Biol., 5 (2001) 447-451]. Antimicrobial Polyurethane Resins have been prepared by incorporating antimicrobial during the synthesis of a resin and the product was suitable for molding into medical devices (U.S. Pat. No. 7,772,296, filed 2007).
Novel supramolecules made from polyethylene oxide copolymers and dendrimers have been examined for delivery of genes and macromolecules [‘Polymer in drug delivery’, O. Pillai and R. Panchagnula, Curr. Opin. Chem. Biol., 5 (2001) 447-451]. Biodegradable Polymer that released fluoroquinolone antibiotic has been developed by conjugating the antibiotic to poly(ε-caprolactone) diol using diisopropylcarbodiimide [S. Y. Han, S. H. Yoon, K. H. Cho, H. J. Cho, J. H. An, and Y. S. Ra, J. Korean Med. Sci., 20 (2005) 297-301]. Polymer barrier layer has been successfully used to effect controlled release of high blood pressure drug Sular (nisoldipine) from its core made from hydroxypropyl methycellulose (HPMC) and the active ingredient (Sciele and SkyePharma). ‘Smart polymers’ have been used to deliver peptide and protein drugs. These can be classified as, temperature sensitive polymers, namely, poly(N-isopropylacryl-amide) (PNIPAAM), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers (PEO-PPO-PEO), poly(ethylene glycol)-poly(lactic acid)-poly(ethylene glycol) triblocks (PEG-PLAPEG); phase sensitive polymers, such as, poly(D,L-lactide), poly(D,L-lactide-co-glycolide) and poly(D,L-lactide-co-e-caprolactone); pH sensitive polymers, such as, anionic pH-sensitive polymers like polyacrylic acid (PAA) (Carbopol®) or its derivatives, polymethacrylic acid (PMAA), poly(ethylene imine), poly(L-lysine), poly(N,N-dimethyl aminoethyl methacryl amide), poly(methacrylic acid-γ-ethylene glycol) P(MAA-g-EG). In the case of most ‘smart polymers’ the peptide/protein drug is physically entrapped within the polymer matrix and slowly released as the polymer degraded. Polymer conjugated anticancer drugs have been studied using polymers such as HPMA [N-(2-hydroxypropyl)methacrylamide] copolymers, PGA [poly(glutamic acid)], PEG [poly(ethylene glycol)] and polysaccharides (e.g. dextran). Details of HPMA copolymer anticancer conjugates and their clinical study has been reviewed [R. Duncan, Biochemical society Transactions, 35, part 1 (2007) 56-60].
In summary, biodegradable polymers for drug delivery purposes are hydrophilic, hydrophobic or a mixture of both, and can also include hydrogels. The therapeutic agent is either physically entrapped during or following the polymerization process or (a) attached covalently to the monomer prior to polymerization and (b) conjugated to a prefabricated polymer via reactive functionalities present on the polymer, on therapeutic agent or both. [Reviews: ‘Drug Delivery Systems, Section 7.14, by J. Heller and A. S. Hoffman, in Biomaterial Science: An introduction to material in medicine, B. D. Ratner (Ed.), 2004//books.googles.com/books; E. W. Neuse, Metal-based Drugs, vol. 2008 (2008), Article ID 469531; A. K. Bajpai, S. K. Shukla, S. Bhanu and S. Kankane, Prog. Polymer Sci., 33 (2008) 1088-1118; R. L. Dunn and R. M. Ottenbrite (Eds), ACS Symp. Series, 469 (1991)].
More recently, ‘click’ chemistry has been used to make polymers from suitably derivatized monomers. The ‘click’ approach for making complex molecules has been described [H. C. Kolb, et al., Angew. Chem., Int. Ed., 40 (2001) 2004-2021] and its applications in making polymeric material has been recently reviewed [A. B. Lowe, Polym. Chem., 1 (2010) 17-36]. Thiol-ene photopolymerization has been used to fabricate PEG-based hydrogels [Biomacromolecules, 9 (2008)1084-1087], and the technique utilized to make protein entrapped, crosslinked, hydrogel preparation for therapeutic end use [A. A. Aimetti, et al., Biomaterials, 30 (2009) 6048-6054].